The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape

Daniel N. Weinberg, Simon Papillon-Cavanagh, Haifen Chen, Yuan Yue, Xiao Chen, Kartik N. Rajagopalan, Cynthia Horth, John T. McGuire, Xinjing Xu, Hamid Nikbakht, Agata E. Lemiesz, Dylan M. Marchione, Matthew R. Marunde, Matthew J. Meiners, Marcus A. Cheek, Michael-Christopher Keogh, Eric Bareke, Anissa Djedid, Ashot S. Harutyunyan, Nada Jabado, Benjamin A. Garcia, Haitao Li, C. David Allis (), Jacek Majewski () and Chao Lu ()
Additional contact information
Daniel N. Weinberg: The Rockefeller University
Simon Papillon-Cavanagh: McGill University
Haifen Chen: McGill University
Yuan Yue: Tsinghua University
Xiao Chen: Columbia University Irving Medical Center
Kartik N. Rajagopalan: Columbia University Irving Medical Center
Cynthia Horth: McGill University
John T. McGuire: Columbia University Irving Medical Center
Xinjing Xu: Columbia University Irving Medical Center
Hamid Nikbakht: McGill University
Agata E. Lemiesz: The Rockefeller University
Dylan M. Marchione: University of Pennsylvania
Matthew R. Marunde: EpiCypher Inc
Matthew J. Meiners: EpiCypher Inc
Marcus A. Cheek: EpiCypher Inc
Michael-Christopher Keogh: EpiCypher Inc
Eric Bareke: McGill University
Anissa Djedid: McGill University
Ashot S. Harutyunyan: McGill University
Nada Jabado: McGill University
Benjamin A. Garcia: University of Pennsylvania
Haitao Li: Tsinghua University
C. David Allis: The Rockefeller University
Jacek Majewski: McGill University
Chao Lu: Columbia University Irving Medical Center

Nature, 2019, vol. 573, issue 7773, 281-286

Abstract: Abstract Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1–4. They are also implicated in human developmental disorders and cancers5–8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9–11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton–Brown–Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.

Date: 2019
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DOI: 10.1038/s41586-019-1534-3

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